How the Immune System Keeps 'Traitor Cells' in Lockdown

Our immune system is charged with the crucial task of keeping us
safe from overwhelming infection. Time and again, our immune cells must
decide very quickly whether they are looking at an invading microbe,
which poses a threat, or a part of the body, which should be protected.

How the Immune System Keeps 'Traitor Cells' in Lockdown

Getting it wrong - and attacking 'self' - can lead to devastating
autoimmune disorders such as rheumatoid arthritis or lupus.

‘The immune system avoids attacking its own tissues with antibodies - whilst still maintaining a strong defense against invaders.’

The immune system avoids
attacking its own tissues with antibodies - whilst still maintaining a
strong defense against invaders, suggests a new Australian research. The findings, from the Garvan Institute
of Medical Research (Sydney) and the John Curtin School of Medical
Research (Australian National University), have just been published in
the leading journal Nature Communications.

The researchers have shown how the immune system can stop 'traitor'
cells - which could otherwise make damaging antibodies against the
body's own tissues (auto-antibodies) - in their tracks.

They show that a type of antibody called Immunoglobulin D or 'IgD'-
which sits on the surface of immune cells termed B cells - is
responsible for stopping the 'traitor' cells from producing
auto-antibodies. IgD keeps the cells in 'lockdown' - unresponsive to the
body's tissues, yet still capable of producing antibodies against
invaders.

The findings solve a longstanding mystery surrounding the function
of IgD, whose role in the immune system has been unclear since it was
first observed 50 years ago.

Professor Christopher Goodnow, Deputy Director of Garvan and Head of
the Immunogenomics laboratory, co-led the research with Dr Anselm
Enders (who leads John Curtin's Immunization Genomics group) and Dr.
Joanne Reed (Garvan).

Prof Goodnow says, "We have known for some time that more than half
of the immune system's B cells are capable of producing damaging
antibodies against the body's own tissues - yet they don't do this. What we haven't understood before is why and how the immune system
keeps these potential 'traitor cells' alive, instead of getting rid of
them completely. Our new research shows that the antibody IgD is the key player in
locking down the traitor cells, so that the immune system can hedge its
bets between discarding these cells and drawing upon them to fight an
infection. By placing the cells that bear autoantibodies in lockdown,
IgD dials down their capacity to produce antibodies against the body's
own tissues - but keeps them alive in case they are needed to fight
invasion by a microbe."

The researchers carried out a detailed study of gene expression
across the whole genome in locked down (or anergic) B cells from mice,
comparing mice with or without functional IgD. The studies revealed a
core set of over 200 genes, one third of which are controlled by IgD,
that together keep the cells unresponsive to the body's own tissues.

Importantly, however, the cells in lockdown are not removed from the
immune system. On the contrary, the researchers found that IgD supports
the cells to accumulate in the spleen and lymph nodes (just as other B
cells do) and, if necessary, to take part in "target training" to make
antibodies against invaders.

"Our experiments have shown that, although IgD places the B cells
that can produce autoantibodies in lockdown, it still promotes the
formation of germinal centers of those muted cells, which is like a
military special operations camp of B cells that begin sharpening their
ability to target an invader when they 'see' one," Dr. Reed says.

The presence of germinal centers is an indication that, under the
right circumstances, the cells are still capable of mounting an attack
against an invader.

"We think that the large-scale lockdown of B cells is the immune
system's way of avoiding 'holes' in its defensive line, so that it is
ready to respond to any conceivable invasion," Prof Goodnow says.

"If every B cell capable of producing autoantibodies was removed,
rather than kept in lockdown, we would severely limit the number of
foreign invaders that our immune system could recognize.

"By locking down B cells, and keeping them alive, IgD strikes a
delicate balance between protection from invaders and avoiding an immune
attack on the body's own tissues."

The findings have personal significance for Prof Goodnow, who in the
late 1980s was the first to describe the presence of an anergic,
unresponsive population of self-reactive B cells in mice.

"To have observed these cells in lockdown, at a point where they
were mysterious to us - and now to be at a point where we can define
with great clarity precisely what's happening in this population of
cells - is a remarkable thing," Prof Goodnow says.

The findings provide a new depth of understanding of the human
immune system and are likely to help cancer researchers understand how B
cells break out of their 'holding pattern' and multiply in common forms
of leukemia and lymphoma.

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